Lysosomal Enzyme Formulation Stabilization via Poloxamer
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Solution Overview
Problem
Existing formulations for lysosomal enzymes, particularly recombinant human α-glucosidase, face challenges such as enzyme precipitation during infusion, leading to filter clogging, reduced therapeutic efficacy, and patient safety concerns, along with stability issues during lyophilization, storage, and shipping.
Innovation Solution
The use of a poloxamer, specifically Pluronic F-68, in formulations to stabilize lysosomal enzymes, prevent precipitation, and enhance stability during lyophilization, reconstitution, storage, and infusion, while also incorporating buffering agents, stabilizing agents, and tonicity modifiers to create a stable pharmaceutical composition for enzyme replacement therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If lysosomal enzymes are formulated for enzyme replacement therapy, then therapeutic efficacy is improved, but enzyme precipitation and aggregation occur during infusion
Solution Approach 1:
The patent introduces poloxamers as intermediary substances that mediate between the lysosomal enzyme and the infusion solution. These poloxamer molecules act as stabilizing agents that prevent direct aggregation of enzyme molecules, allowing the enzyme to remain soluble and stable during infusion while maintaining its therapeutic activity.
Solution Approach 2:
The patent modifies formulation parameters by adjusting pH, adding buffering agents, and incorporating stabilizing agents like poloxamers. These parameter changes create a formulation environment that prevents enzyme precipitation and aggregation, resolving the contradiction between maintaining therapeutic efficacy and preventing harmful aggregation.
2Productivity
If lysosomal enzymes are stored and shipped, then availability is improved, but stability is compromised during lyophilization and storage
Solution Approach 1:
The patent applies preliminary protective measures during formulation and lyophilization by incorporating stabilizing agents and buffering agents before storage. This preliminary action prevents degradation during the storage and shipping process, allowing the enzyme to maintain stability while being available for future use.
Solution Approach 2:
The patent optimizes formulation parameters including pH buffering and the addition of stabilizing agents to create a formulation that remains stable during lyophilization and storage. These parameter changes ensure the enzyme maintains its structural integrity and activity throughout the product lifecycle from manufacturing to storage.
3Reliability
If enzyme concentration is increased for therapeutic effect, then efficacy is improved, but precipitation and filter clogging worsen
Solution Approach 1:
The patent uses poloxamers as intermediary stabilizing agents that allow higher enzyme concentrations to be formulated without causing precipitation or filter clogging. These intermediaries maintain solubility and prevent aggregation even at elevated concentrations, enabling effective therapy without the harmful effects of high concentration.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulations significantly reduce enzyme precipitation and enhance stability, ensuring effective delivery and prolonged shelf life, thereby improving therapeutic efficacy and patient safety by maintaining enzyme activity and preventing aggregation.
Implementation Method 1
the use of a poloxamer, specifically Pluronic F-68, in formulations to stabilize lysosomal enzymes, prevent precipitation
Implementation Method 2
In some embodiments, a pharmaceutical composition according to the invention further includes a buffering agent. In some embodiments, the buffering agent is selected from the group consisting of histidine, sodium acetate, citrate, phosphate, succinate, Tris and combinations thereof.
Implementation Method 3
In some embodiments, a pharmaceutical composition according to the invention further includes a stabilizing agent. In some embodiments, the stabilizing agent is selected from the group consisting of sucrose, arginine, sorbitol, mannitol, glycine, trehalose and combinations thereof.
Data Source
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AI summary
The present invention provides improved formulations for lysosomal enzymes useful for enzyme replacement therapy. Among other things, the present invention provides formulations that preserve or enhance the stability and/or efficacy of a lysosomal enzyme such as acid alpha-glucosidase.